This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Project Summary CXCR4 chemokine receptors are found on the surface of immune cells, and together with the specific natural ligand, stromal cell-derived factor-1[unreadable] (SDF-1[unreadable]), have been revealed to play a role in a number of disease states. For example, the CXCR4[unreadable]SDF-1[unreadable] system has involvement in cancer progression and metastasis, and the development of rheumatoid arthritis. Also, within the last ten years the CXCR4 and CCR5 co-receptors have been revealed as the entry route for HIV into cells, generating interest in a new therapeutic approach to treatment via entry inhibitor drugs rather than the current preference for reverse transcriptase and protease inhibitors. Our aim is to develop new antagonists for the CXCR4 co-receptor. They are conformationally fixed macrocyclic compounds and their transition metal complexes. The unrestrained macrocyclic equivalent is a known CXCR4 antagonist that has been clinically tested for anti-HIV efficacy as well as its utility in facilitating stem cell transplantation. The conformational fixing we propose should lead to improved CXCR4 binding, as well as illuminating the structural requirements for binding transition metal complexes to this important chemokine receptor. We have already demonstrated the utility of our synthetic schemes by successfully producing the initial target molecules for both of our proposed types of conformational fixing. These lead compounds have also been screened for CXCR4 binding using flow cytometry methods to quantify the inhibition of known CXCR4-binding antibodies by our antagonists in immune cells which overexpress the CXCR4 receptor. We now request support to complete the synthesis and testing of a series of compounds, and gain further insights into the essential design features for this drug class through spectroscopic and biological studies. Relevance Chemokines and their receptors are involved in multiple diseases, including AIDS and cancer. We intend to produce molecules that will specifically target the CXCR4 receptor, and then study how efficiently these new molecules bind this target. Results may include new tools for researchers or new medicines themselves.